While the cause of systemic lupus erythematosus (SLE) remains unknown, the role of anti-DNA antibodies in the progression of SLE has been recognized for over three decades. Specific determinants on DNA recognized by pathogenic anti-DNA antibodies remain to be elucidated. Difficulty in identifying these elements stems from antibody heterogeneity in SLE patients and from the technical challenges of required experiments. Work by others using anti-idiotypic antibodies against anti-DNA antibodies suggests that despite this heterogeneity a small number of combining sites is responsible for SLE pathology. Recent advances using random oligonucleotide selection strategies to identify specific recognition elements for proteins suggest a solution to the problem of pathogenic anti-DNA antibody determinant identification. Preliminary work using IgG from a lupus mouse (BXSB) indicates that random selection is appropriate for identifying anti-DNA antibody determinants. Using purified IgG from SLE patients with nephritis, we propose to identify the major DNA sequence determinants specific for pathogenic anti-DNA antibodies and to ascertain the reactivity of these determinants among SLE patients. Ultimately, determinants that are widely recognized by patient IgGs will be used as lead compounds to design drugs that block formation of damaging immune complexes and inhibit production of pathogenic antibodies in SLE patients.